EP1662908A1 - Zusammensetzung und verfahren zur förderung der knochenheilung - Google Patents

Zusammensetzung und verfahren zur förderung der knochenheilung

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Publication number
EP1662908A1
EP1662908A1 EP04740254A EP04740254A EP1662908A1 EP 1662908 A1 EP1662908 A1 EP 1662908A1 EP 04740254 A EP04740254 A EP 04740254A EP 04740254 A EP04740254 A EP 04740254A EP 1662908 A1 EP1662908 A1 EP 1662908A1
Authority
EP
European Patent Office
Prior art keywords
vitamin
nutritional composition
lysine
bone
proline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP04740254A
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English (en)
French (fr)
Other versions
EP1662908B9 (de
EP1662908B1 (de
Inventor
Matthias Rath
Shrirang Netke
Waheed M. Roomi
Vadim Ivanov
Aleksandra Niedzwiecki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RATH, MATTHIAS, DR. MED.
Original Assignee
Rath Matthias Dr med
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Publication date
Application filed by Rath Matthias Dr med filed Critical Rath Matthias Dr med
Priority to PL04740254T priority Critical patent/PL1662908T3/pl
Publication of EP1662908A1 publication Critical patent/EP1662908A1/de
Application granted granted Critical
Publication of EP1662908B1 publication Critical patent/EP1662908B1/de
Publication of EP1662908B9 publication Critical patent/EP1662908B9/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention generally relates to nutritional compositions for facilitating bone healing and uses thereof.
  • Bone is a dynamic living tissue and is continuously being replenished by reso ⁇ tion and deposition of bone matrix.
  • the stability of bone depends upon the underlying connective tissue.
  • Oxlund H. et al. has shown that optimally structured collagen is more important for bone strength than bone compactness and its calcium saturation (Bone 1996; 19:479-84).
  • a concentration of cross-links between collagen strands appeared 30% less in bone affected by osteoporosis.
  • Knot L. et al. has shown that collagen structure and spatial organization of its fiber network is critical for deposition of minerals and compactness in the bone, and that the micro-architecture of collagen determines bone strength (Bone 1998; 22:181-7).
  • the healing process after bone fracture is an orderly process that involves multiple phases including: i) hematoma formation; ii) fibro-cartilaginous callus formation; iii) bony callus formation; and iv) bone remodeling.
  • pluripotential cells in the vicinity of the bone fracture differentiate into osteoblasts and chondrocytes. Osteoblasts origin form osteoid tissues and they lay down collagen fibers. Chondrocytes give rise to hypertrophic chondrocytes that deposit a mineralized matrix to form calcified cartilage, which is then remodeled into compact bone.
  • U.S. Pat. 6,258,778 discloses a method of enhancing bone and cartilage repair by administering angiotensin and its analogues.
  • U.S. Pat. 5,502,074 discloses a method of facilitating bone healing using benzothiophenes. The safety of use of these drugs are not established. For example, angiotensin is known to exert potent cardiovascular and renal effects, and its use in patients with heart or renal failure may be limited.
  • U.S. Pat. 6,061,597 discloses the application of resonant frequency stimulation to promote fracture healing.
  • U.S. Pat. 6,290,714 discloses a low level laser therapy in treating bone fracture. The effectiveness of these approach is not shown and requires expensive medical office visits and/or computer equipment. None of these methods has been clinically proven.
  • U.S. Pat. 5,232,709 discloses a nutritional supplement having a large dose of calcium in treating bone loss. Administering to a bone fractured individual with a large dose of calcium would cause mineralization of the bone tissue, rather than supplementing bone collagen. The increased bone mineralization causes further hardening of bone. The affected bone becomes more brittle over time, making it prone to compound fractures and shattering under stress.
  • the present invention relates to a nutritional composition
  • a nutritional composition comprising lysine, proline, ascorbic acid, copper, and vitamin $ .
  • the nutritional composition is suitable for human use and is effective in facilitating bone healing.
  • the nutritional composition is also suitable for animal use.
  • said animal is mammal, most preferably a dog, cat or horse.
  • the nutritional composition contains 27-34 % wt lysine, 14-15 % wt proline, and 42-47 % wt ascorbic acid.
  • the nutritional composition is administered orally.
  • the recommended amount is 1,010 mg - 8 gram lysine, 560 mg - 4 gram proline, 1,500 mg - 9 gram ascorbic acid, 2 ⁇ g - 6 mg copper, and 0.5 mg - 10 mg vitamin B 6. More preferably, a recommended amount is 230 mg - 10 gram lysine, 120 mg - 5 gram proline, 360 mg - 15 gram ascorbic acid, 1.5 ⁇ g - 20 mg copper, and 0.2 mg - 20 mg vitamin B 6 . Most preferably, a recommended amount is 1,010 mg lysine, 560 mg proline, 1,500 mg ascorbic acid, 330 ⁇ g copper and 10 mg vitamin B 6 .
  • the nutritional composition is a daily dosage (based on a human subject of average body weight of 72 kg) of 3.2 - 139 mg/kg lysine, 1.7 - 69.4 mg/kg proline, 5 - 208.3 mg/kg ascorbic acid, 0.02 - 278 ⁇ g/kg copper, 2.78 - 279 ⁇ g kg vitamin B 6 .
  • the nutritional composition is a daily dosage of 14 - 111 mg kg lysine, 7.8 - 55.6 mg/kg proline, 20.8 - 125 mg/kg ascorbic acid, 0.03 - 83.3 ⁇ g kg copper, and 6.94 - 139 ⁇ g/kg vitamin B 6 .
  • the nutritional composition is a daily dosage of 14 mg/kg lysine, 7.8 mg kg proline, 20.8 mg/kg ascorbic acid, 4.6 ⁇ g/kg copper, 139 ⁇ g/kg vitamin B 6 .
  • the nutritional composition further comprises vitamin A, vitamin D , vitamin E, vitamin Bi, vitamin B 2 , niacin, folic acid, vitamin B 12 , biotin, pantothenic acid, calcium, phosphorus, magnesium, zinc, selenium, manganese, chromium, molybdenum, potassium, citrus fruit peel bioflavanoids, arginine, cysteine, inositol, carnitine, coenzyme Qio, and pycnogenol.
  • the recommended amount is 67 ⁇ g -100 mg vitamin A, 0.7 ⁇ g - 50 ⁇ g vitamin D 3 , 0.7 ⁇ g - 50 ⁇ g vitamin E, 1.4 mg - 8 mg vitamin Bi, 1.4 mg - 8 mg vitamin B 2 , 9 mg - 250 mg niacin, 18 ⁇ g - 500 ⁇ g folic acid, 4 ⁇ g - 100 ⁇ g vitamin B ⁇ 2 , 13 ⁇ g - 400 ⁇ g biotin, 8 mg - 100 mg pantothenic acid, 7 mg - 40 mg calcium, 3 mg - 300 mg phosphorus, 40 mg - 200 mg magnesium, 0.5 mg - 10 mg zinc, 20 ⁇ g - 300 ⁇ g selenium, 0.8 mg - 15 mg manganese, 2 ⁇ g - 200 ⁇ g chromium, 0.8 ⁇ g - 100 ⁇ g molybdenum, 4 mg - 300 mg potassium, 20 mg - 500 mg citrus fruit peel bioflavanoids
  • the recommended amount is 166 ⁇ g -50 mg vitamin A, 1.65 ⁇ g - 20 ⁇ g imin D 3 , 1.65 ⁇ g - 20 ⁇ g vitamin E, 3.5 mg - 7 mg vitamin Bi, 3.5 mg - 7 mg vitamin B 2; 5 mg - 100 mg niacin, 45 ⁇ g - 300 ⁇ g folic acid, 10 ⁇ g - 50 ⁇ g vitamin B ⁇ 2 , 32 ⁇ g - 300 biotin, 20 mg - 60 mg pantothenic acid, 17 mg - 35 mg calcium, 7 mg - 100 mg (sphorus, 50 mg - 100 mg magnesium, 3 mg - 8 mg zinc, 30 ⁇ g - 250 ⁇ g selenium, 1 mg .25 mg manganese, 2 ⁇ g - 75 ⁇ g chromium, 2 ⁇ g - 75 ⁇ g molybdenum, 8 mg - 200 mg assium, 50 mg - 250 mg citrus fruit peel bioflavanoids, 100 mg
  • the recommended amount is 333 ⁇ g vitamin A, 3.3 ⁇ g vitamin D 3 , 3.3 ⁇ g imin E, 7 mg vitamin Bi, 7 mg vitamin B 2 , 45 mg niacin, 90 ⁇ g folic acid, 20 ⁇ g vitamin , 65 ⁇ g biotin, 40 mg pantothenic acid, 35 mg calcium, 15 mg phosphorus, 40 mg gnesium, 7 mg zinc, 20 ⁇ g selenium, 1.3 mg manganese, 10 ⁇ g chromium, 4 ⁇ g lybdenum, 20 mg potassium, 100 mg citrus fruit peel bioflavanoids, 40 mg arginine, 35 mg teine, 35 mg inositol, 35 mg carnitine, 7 mg coenzyme Qio, and 7 mg pycnogenol.
  • the nutritional composition comprises a daily dosage (based on a human subject of rage body weight of 72 kg) of 0.9-1,390 ⁇ g/kg vitamin A, 0.01-0.694 ⁇ g/kg vitamin D 3 , 1-0.694 ⁇ g/kg vitamin E, 19.4-111 ⁇ g/kg vitamin B ⁇ 19.4-111 ⁇ g/kg vitamin B 2> 125-3,472 kg niacin, 0.25-6.94 ⁇ g/kg folic acid, 0.05-1.39 ⁇ g/kg vitamin B, 2 , 0.181-5.56 ⁇ g/kg tin, 111-1,390 ⁇ g/kg pantothenic acid, 97.2-555 ⁇ g/kg calcium, 42-4,167 ⁇ g/kg )sphorus, 555-2,778 ⁇ g/kg magnesium, 6.9-139 ⁇ g/kg zinc, 0.28-4.17 ⁇ g/kg selenium, 1-208.3 ⁇ g/kg manganese, 0.03-2.78 ⁇ g
  • the nutritional composition comprises a daily dosage (based on a human )ject of average body weight of 72 kg) of 2.31-694 ⁇ g/kg vitamin A, 0.023-0.278 ⁇ g/kg amin D 3 , 0.023-0.278 ⁇ g/kg vitamin E, 48.6-97.2 ⁇ g kg vitamin Bi, 48.6-97.2 ⁇ g/kg amin B 2, 312.5-3,190 ⁇ g/kg niacin, 0.6-4.17 ⁇ g/kg folic acid, 0.14-0.69 ⁇ g/kg vitamin B ⁇ 2> 44-4.17 ⁇ g/kg biotin, 278-833 ⁇ g/kg pantothenic acid, 236-903 ⁇ g/kg calcium, 97.2-1,390 /kg phosphorus, 694-1,390 ⁇ g/kg magnesium, 41.7-111 ⁇ g/kg zinc, 0.42-3.47 ⁇ g/kg enium, 13.9-45.1 ⁇ g/kg manganese, 0.07-2.78
  • the nutritional composition comprises a daily dosage (based on a human subject of average body weight of 72 kg) of 4.6 ⁇ g/kg vitamin A, 0.046 ⁇ g/kg vitamin D 3 , 0.046 ⁇ g/kg vitamin E, 97.2 ⁇ g/kg vitamin Bi, 97.2 ⁇ g/kg vitamin B , 625 ⁇ g/kg niacin, 1.25 ⁇ g/kg folic acid, 0.27 ⁇ g/kg vitamin B ⁇ 2 , , 0.9 ⁇ g/kg biotin, , 555 ⁇ g/kg pantothenic acid, 486 ⁇ g/kg calcium, 208 ⁇ g/kg phosphorus, 555 ⁇ g/kg magnesium, 97.2 ⁇ g/kg zinc, 0.78 ⁇ g/kg selenium, 18.1 ⁇ g/kg manganese, 0.14 ⁇ g/kg chromium, 0.06 ⁇ g/kg molybdenum, 277.8 ⁇ g/kg potassium, 1,389 ⁇ g/kg citrus fruit
  • the present invention provides a method for facilitating bone healing in a mammal, comprising the step of administering to a mammal in need thereof an effective amount of a nutritional composition comprising lysine, proline, ascorbic acid, copper, and vitamin B 6 .
  • the mammal is a human.
  • the nutritional composition is effective in reducing healing time for bone fractures, referably, the healing time is reduced > about 5%. More preferably, the healing time is ;duced > about 15%. Most preferably, the healing time is reduced >about 50%.
  • the nutritional composition is effective in human of all ages.
  • the utritional composition is suitable for facilitating bone healing in adults of 41-40 and 41-50 sars of age.
  • the nutritional composition provides a 37 % and 40% reduction in healing time :spectively. More preferably, the nutritional composition is effective in human of 10-20 ears of age (i.e., adolescents), which provides a 49% reduction in healing time.
  • the nutritional composition may be administered orally, intravenously, or arenterally.
  • bone healing refers to the healing of bone fractures. Bone healing lall also encompass the process of bone repair and shall not be limited to healing of :cidental bone fractures. Bone healing also concerns surgical intervention of bones such as one replacement (e.g., hip and knee joint replacement) and bone implantation (e.g., tooth nplantation). When a bone is healed, the normal mobility at the fractured bone site is :stored and there is absence of pain elicited by stressing the fracture or by walking and eneral restoration of efficient and painless functioning of the affected limb at the fracture ite.
  • one replacement e.g., hip and knee joint replacement
  • bone implantation e.g., tooth nplantation
  • healing time refers to the time elapsed from the time when bone fracture occurs ntil the time when the bone fracture is healed. With respect to the experiments performed in le studies disclosed herein, the healing time is measured for the time elapsed from the time f reduction of fractured bone until the bone is healed.
  • Reduction refers to the process of ligning the tips of a fractured bone (e.g., tibia) at the point of fracture in a position to allow using of the fractured bone tips together.
  • Adolescent is a human between about 10 and bout 20 years of age.
  • Effectivee amount refers to an amount of the present nutritional omposition effective in reducing the healing time of bone fracture.
  • “Pharmaceutically cceptable” refers to carriers, diluents, and excipients that are compatible with the other igredients of the formulation, and not deleterious to the recipient thereof.
  • “% wt” refers to % f a specific ingredient as a % proportion to the total weight of the nutritional composition, r example, 27 % wt of lysine refers to a nutritional composition in which 27 % of the total eight of the nutritional composition is lysine.
  • e present nutritional composition is suitable for use in a mammal.
  • the mammal a human. Different age groups of human may exhibit different speeds of bone healing.
  • human of elder age may be easier to suffer from bone fracture (due to calcification by osteoporosis) and is likely to have a longer healing time.
  • the present ltritional composition is found to be effective in faciliating bone healing in human in :neral; and not particularly limited to a particular age group.
  • ⁇ e present invention provides a nutritional composition for facilitating bone healing in iman, preferably in adolescent individuals, comprising the step of administering to a human need of treatment an effective amount of the composition comprising lysine, proline, icorbic acid, copper, and vitamin B 6
  • the nutritional composition contains 27-34 i wt lysine, 42-47 % wt ascorbic acid and 14-15 % wt proline.
  • l e present nutritional composition also contains lysine and proline.
  • Lysine and proline are )nstituents of collagen and proteins in the bone. Lysine and proline may contribute to steoblast proliferation of alkaline phosphatase, nitric oxide, insulin like growth factor-I, and )llagen type I and may be essential for proper bone formation.
  • ysine may include lysine salts such as hydroxylysine and hydroxylysine salts.
  • a daily dose f 3.2 - 139 mg/kg lysine is recommended.
  • 14 to 111 mg kg lysine is used; and lore preferably, 14 mg/kg lysine is used.
  • the daily commended dosage of lysine is 230 mg to 10 grams; preferably, 1,010 mg to 8 grams; and tore preferably 1,010 mg.
  • roline is a non-essential amino acid.
  • its synthesis in human body could be limited rider certain conditions. It has been reported that the stress of fracture lowers non-essential mino acid levels in plasma of elder humans. In such a case, deficiency of proline, a semi- ssential amino acid, if any, would adversely affect the healing of fracture, since this amino :id is present in a large proportion in collagen.
  • roline may include proline salts such as hydroxyproline and hydroxyproline salts.
  • proline salts such as hydroxyproline and hydroxyproline salts.
  • a daily ose of 1.7- 69.4 mg/kg proline is recommended.
  • 7.8 to 56 mg/kg is used; and nore preferably, 7.8 mg/kg is used.
  • the daily ecommended dosage of proline is 120 mg to 5 grams; preferably, 560 mg to 4 grams; and lore preferably 560 mg.
  • Tie present nutritional composition contains ascorbic acid.
  • Ascorbic acid may promote the •regressive development of osteoblast phenotype and facilitate bone healing and it is also lecessary for the differentiation and proliferation of osteogenic and chondrogenic cells.
  • ascorbic acid and vitamin C are used interchangeably.
  • the term ascorbic acid encompasses iscorbic acid and salts thereof.
  • the ascorbic acid to be applied in accordance with he present invention is calcium ascorbate, magnesium ascorbate or ascorbyl palmitate.
  • a laily dose of 5 - 208 mg/kg ascorbic acid is recommended.
  • 20.8 - 125 mg/kg is ised; and more preferably, 20.8 mg/kg is used.
  • the laily recommended dosage of ascorbic acid is 360 mg to 15 grams; preferably, 1,500 mg to 9 frams; and more preferably 1,500 mg.
  • the present invention further provides a nutrient composition further comprising minerals in ⁇ Vor trace elements.
  • Trace elements may help to catalyze the production of these nacromolecules needed for connective tissue structure and function.
  • Preferred trace elements n accordance with the present invention are iron, iodine, copper, zinc, manganese, cobalt, nolybdenum, selenium, chromium, nickel, tin, fluorine or vanadium.
  • Hopper as a cofactor for lysyl oxidase, is essential for intra- and intermolecular cross-links in :ollagen. Copper deficit has been shown to impair the mechanical strength of bone, t was hypothesized that a relatively large quantity of ascorbic acid, vitamin Be, L-lysine and ..-proline, together with copper, would have a pronounced effect on bone collagen health and ilinction to produce a marked difference in healing time between fractured bones of a supplement group and a placebo group.
  • Copper compounds may include copper glycinate.
  • a daily dose of 0.02 to 278 ⁇ g/kg copper is recommended.
  • Preferably, 0.03 to 83 ⁇ g/kg is used; and more preferably, 4.6 ⁇ g/kg is used.
  • the daily recommended dosage 1.5 ⁇ g to 20 mg; preferably 2 ⁇ g to 6 mg; and more preferably, 330 ⁇ g.
  • Vitamin B 6 is of importance in bone healing, as it is instrumental in providing reducing equivalents necessary for mineralization. Vitamin B 6 deficiency caused marked diminution in glucose 6-phosphate dehydrogenase activity in perisoteal bone formation and in developing callus. It also caused changes in the bone suggestive of imbalance between osteoblasts and osteoclasts.
  • Vitamin B 6 compounds may include pryridosine HCl.
  • a daily dose of 2.8 to 279 ⁇ g/kg vitamin B is recommended.
  • Preferably, 7 to 139 ⁇ g/kg vitamin B 6 is used; and more preferably, 139 ⁇ g/kg is used.
  • the daily recommended dosage of vitamin B 6 is 0.2 to 20 mg; preferably, 0.5 to 10 mg; and more preferably, 10 mg.
  • Certain ingredients of the nutritional composition according to the invention are present at a high amount. Specifically, lysine is present between 27-34 % wt (preferably at 28 - 33 % wt); proline is present between 14 - 16 % wt (preferably 15-16 % wt); and ascorbic acid is present between 42-47 % wt (preferably at 43-46 % wt).
  • a nutritional composition as specified herein efficiently facilitates bone healing (i.e. it reduces the healing time) of bone fractures in humans, particularly in adolescents.
  • administration of the nutritional composition of the present invention does not merely facilitate bone healing efficiently, but also improves general well being, and is cost effective.
  • a recommended daily oral dosage includes 3.2-139 mg/kg lysine, 1.37-69 mg/kg proline, 5- 208 mg/kg ascorbic acid, 2.78-279 ⁇ g/kg vitamin B 6 , and 0.02-278 ⁇ g/kg copper.
  • the recommended daily oral dosage is: 14-111 mg/kg lysine, 7.8 - 56 mg/kg proline, 20.8-125 mg/kg ascorbic acid, 6.9-139 ⁇ g/kg vitamin Be, and 0.03-83 ⁇ g/kg copper.
  • the recommended daily oral dosage is: 14 mg/kg lysine, 7.8 mg/kg proline, 20.8 mg/kg ascorbic acid, 139 ⁇ g/kg vitamin B 6 , 4.6 ⁇ g/kg copper.
  • the nutritional composition is administered 3 tablets per day (i.e., one tablet in morning, one tablet in afternoon and one tablet at night).
  • the present nutritional composition may further comprise vitamin D 3 , manganese, arginine, cysteine, vitamins A, E, Bi, B 2 , B ⁇ 2 , niacin, folic acid, biotin, pantothenic acid, calcium, phosphorus, magnesium, zinc, selenium, chromium, molybdenum, potassium, citrus fruit peel bioflavanoids, inositol, carnitine, coenzyme Qio, and pycnogenol.
  • vitamin D 3 manganese, arginine, cysteine, vitamins A, E, Bi, B 2 , B ⁇ 2 , niacin, folic acid, biotin, pantothenic acid, calcium, phosphorus, magnesium, zinc, selenium, chromium, molybdenum, potassium, citrus fruit peel bioflavanoids, inositol, carnitine, coenzyme Qio, and pycnogenol.
  • the particular dosage of the present nutritional composition required to facilitate bone healing will depend on the severity of the medical condition, the route of administration and the particular subject being treated.
  • the nutritional composition of the present invention may be administered by a variety of routes including oral, intravenous, or parenteral administration.
  • the nutritional composition is in unit dosage form, e.g. tablets or capsules.
  • the present nutritional composition is recommended to be administered as an orally tablet preparation.
  • a daily recommended dosage (based on a human subject of average body weight of 72 kg) may further contain 0.9-1,390 ⁇ g/kg vitamin A, 0.01-0.694 ⁇ g/kg vitamin D 3 , 0.01-0.694 ⁇ g/kg vitamin E, 19.4-111 ⁇ g/kg vitamin Bj, 19.4-111 ⁇ g/kg vitamin B 2 , 125-3,472 ⁇ g/kg niacin, 0.25-6.94 ⁇ g/kg folic acid, 0.05-1.39 ⁇ g/kg vitamin B [2 , 0.181-5.56 ⁇ g/kg biotin, 111- 1,390 ⁇ g/kg pantothenic acid, 97.2-555 ⁇ g/kg calcium, 42-4,167 ⁇ g/kg phosphorus, 555- 2,778 ⁇ g/kg magnesium, 6.9-139 ⁇ g/kg zinc, 0.28-4.17 ⁇ g/kg selenium, 11.1-208.3 ⁇ g/kg manganese, 0.03-2.78
  • the daily recommended dosage (based on a human subject of average body weight of 72 kg) may further contain 2.31-694 ⁇ g/kg vitamin A, 0.023-0.278 ⁇ g/kg vitamin D 3 , 0.023-0.278 ⁇ g/kg vitamin E, 48.6-97.2 ⁇ g/kg vitamin Bj, 48.6-97.2 ⁇ g/kg vitamin B 2> 312.5- 3,190 ⁇ g/kg niacin, 0.6-4.17 ⁇ g/kg folic acid, 0.14-0.69 ⁇ g/kg vitamin B ⁇ 2 , 0.444-4.17 ⁇ g/kg biotin, 278-833 ⁇ g/kg pantothenic acid, 236-903 ⁇ g/kg calcium, 97.2-1,390 ⁇ g/kg phosphorus, 694-1,390 ⁇ g/kg magnesium, 41.7-111 ⁇ g/kg zinc, 0.42-3.47 ⁇ g/kg selenium, 13.9-45.1 ⁇ g/kg manganese, 0.07-2.78
  • the nutritional composition may further include a daily dosage (based on a uman subject of average body weight of 72 kg) of 4.6 ⁇ g/kg vitamin A, 0.046 ⁇ g/kg vitamin '3, 0.046 ⁇ g/kg vitamin E, 97.2 ⁇ g/kg vitamin Bi, 97.2 ⁇ g/kg vitamin B 2> 625 ⁇ g/kg niacin, 25 ⁇ g/kg folic acid, 0.27 ⁇ g/kg vitamin Bj 2 , , 0.9 ⁇ g/kg biotin, , 555 ⁇ g/kg pantothenic acid, 86 ⁇ g/kg calcium, 208 ⁇ g/kg phosphorus, 555 ⁇ g/kg magnesium, 97.2 ⁇ g/kg zinc, 0.78 g/kg selenium, 18.1 ⁇ g/kg manganese, 0.14 ⁇ g/kg chromium, 0.06 ⁇ g/kg molybdenum, 77.8 ⁇ g/kg potassium, 1,389 ⁇ g/kg citrus fruit peel
  • he present nutritional composition may include a pharmaceutically acceptable carrier, iluent, or excipient.
  • Nutritional composition of the present invention can be prepared by rocedures known in the art. Respective ingredients may be formulated with common xcipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and le like.
  • excipients, diluents, and carriers include: i) fillers and extenders such as tarch, sugars, mannitol, and silicic derivatives; ii) binding agents such as carboxymethyl ellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone; iii) loisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and odium bicarbonate; agents for retarding dissolution such as paraffin; iv) reso ⁇ tion ccelerators such as quaternary ammonium compounds; v) surface active agents such as cetyl alcohol, and glycerol monostearate; v) adso ⁇ tive carriers such as kaolin and bentonite; nd vi) lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.
  • fillers and extenders such as tarch, sugars, mannito
  • Tie nutritional compositions may also be formulated as elixirs or solutions for convenient iral administration or as solutions appropriate for parenteral administration, for example, by ntramuscular, subcutaneous or intravenous routes.
  • the formulation is in the form of a pill, tablet, capsule, lozenge, liquid or similar dosage form.
  • the nutritional compositions may well be suited to formulation as sustained release dosage forms and the like.
  • the ingredients listed in Table 1 were formulated to form tablets.
  • the tablets contained the key ingredients of lysine (1,010 mg), proline (560 mg), ascorbic acid (1,500 mg), copper (330 ⁇ g) and vitamin B ⁇ (10 mg).
  • the tablets further contained additional ingredients including vitamin D 3 , manganese, arginine, cysteine, vitamins A, E, B B 2 , B ⁇ 2 , niacin, folic acid, biotin, pantothenic acid, calcium, phosphorus, magnesium, zinc, selenium, chromium, molybdenum, potassium, citrus fruit peel bioflavanoids, inositol, carnitine, coenzyme Qio, and pycnogenol.
  • additional ingredients including vitamin D 3 , manganese, arginine, cysteine, vitamins A, E, B B 2 , B ⁇ 2 , niacin, folic acid, biotin, pantothenic acid, calcium, phosphorus, magnesium, zinc, selenium, chromium, molybdenum, potassium, citrus fruit peel bioflavanoids, inositol, carnitine, coenzyme Qio, and pycnogenol.
  • lody Weight refers to a human subject of average body weight of 72 kg
  • dmitted patients were either receive standard care and placebo or standard care with ipplementation with a nutritional supplement comprising lysine, proline, ascorbic acid, ipper and vitamin B 6 .
  • Qualifying patients, on admssion to the study, were clinically :amined and the radiographs of the affected limbs were taken, fractures reduced under lesthesia and above knee plaster casts applied.
  • Values in parenthesis represent percentage of total patients in the specified age group
  • Jl fractures were reduced (closed reduction) under anesthesia and above knee plaster casts pplied.
  • the fractured limbs were routinely radiographed before and after reduction.
  • the iipplemented group of patients were supplied with the nutritional composition in Table 1 and le placebo group of patients with bottles containing placebo tablets.
  • the nutritional omposition listed in Table 1 were studied to evaluate if the proposed desired supplements an ensure adequacy of nutrients impacting fracture healing.
  • the placebo tablets contained laterial of no medical significance, such as cellulose, fructose etc., but were physically idistinguishable from nutrient tablets. All patients were asked to take one tablet thrice daily norning, afternoon and night) .
  • Healing was defined as absence of abnormal mobility at the fracture site linically and absence of pain elicited by stressing the fracture or by walking. Radiographic onfirmation of callus formation was used as supporting evidence for healing. (See Figures 1 d 2 for radiographic examples). A healing period of greater than 20 weeks without any rgical intervention was considered delayed healing.
  • the age range of the patients in the pplemented group was between 15 to 65 years, with a mean age of 35 years.
  • the age range the patients in the placebo group was between 12 to 75 years, with a mean age of 32 years.
  • the le healing time of the patients is detailed in Table 4.
  • the mean healing time for the patients the supplemented group was 14.0+1.1 weeks.
  • the mean healing time for the patients in the acebo group was 16.9+ 1.2 weeks.
  • the healing time of bone fracture in patients of different ages is shown in Table 6.
  • the healing time reduced from 17.6 weeks to 9 weeks (reduced +9 %).
  • the healing time reduced from 17.1 weeks to 10.7 weeks (reduced 37%).
  • the healing time reduced from 21.2 weeks to 12.7 weeks (reduced 40%).
  • the iling time reduced from 16 weeks to 15.7 weeks (reduced 1.8%).
  • the healing time the supplemented group except in the 21-30 year old group, is reduced. (Table 5). ble 5 - Healing Time (in Weeks) for Various Age Groups
  • ⁇ e data suggest that administering to patients suffering from bone fracture with the present tritional composition at the specified doses effectively reduces the healing time by at least o weeks in 75% of the patients.
  • Patients in the supplemented group also reported an hanced feeling of general well being during the study. The strongest effects can be seen in ; adolescent age group (i.e., 10 to 20 years of age) who has a 49% reduction in the healing tie. Patients who are 41-50 years and 31-40 years of age also have a significant reduction in ; healing time (i.e., 40 % and 37%, respectively). It is believed that patients in the other age Dups may likely to receive the same benefits if the dosage of the nutritional supplementation optimized.
  • igure 1 depicts a radiograph of tibial shaft fracture immediately prior to reduction.
  • igure 2 depicts radiograph of tibial shaft fracture at healing at 12 weeks.
  • igure 3 depicts ascorbic acid levels (urinalysis) in supplemented (patient #1-29) and placebo jatient #30-70) groups.
  • igure 4 depicts a distribution of patients (percentage) by tibial fracture healing time.

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